Additional Results from Two Randomized, Placebo-Controlled Trials of Stiripentol in Dravet Syndrome Highlight a Rapid Antiseizure Efficacy with Longer Seizure-Free Periods.

INTRODUCTION: The efficacy of stiripentol in Dravet syndrome children was evidenced in two randomized, double-blind, placebo-controlled, phase 3 studies, namely STICLO France (October 1996-August 1998) and STICLO Italy (April 1999-October 2000), but data were not fully exploited at the time. METHODS: This post-hoc analysis used additional information, notably collected during the open-label extension (OLE) month, or reported by caregivers in individual diaries, to evaluate new outcomes. RESULTS: Overall, 64 patients were included (31 in the placebo group, 33 in the stiripentol group) of whom 34 (53.1%) were female. Patients' mean and median (25%; 75%) age were 9.2 years (range 3.0-20.7 years) and 8.7 years (6.0; 12.1) respectively. At the end of the double-blind treatment period, 72% of the patients in the stiripentol group had a ≥ 50% decrease in generalized tonic-clonic seizure (GTCS) frequency, versus 7% in the placebo group (P < 0.001), 56% had a profound (≥ 75%) decrease versus 3% in the placebo group (P < 0.001), and 38% were free of GTCS, but none in the placebo group (P < 0.001). The onset of stiripentol efficacy was rapid, significant from the fourth day of treatment onwards. The median longest period of consecutive days with no GTCS was 32 days in the stiripentol group compared to 8.5 days in the placebo group (P < 0.001). Further to the switch to the third month OLE, an 80.2% decrease in seizure frequency from baseline was observed in patients previously receiving placebo, while no change in efficacy was observed in those already on stiripentol. Adverse events were more frequent in the stiripentol group, with significantly more episodes of somnolence, anorexia, and weight decrease than in the placebo group. CONCLUSION: Altogether these new analyses of the STICLO data reinforce the evidence for a remarkable efficacy of stiripentol in Dravet syndrome, with a demonstrated rapid onset of action and sustained response, as also evidenced in further post-randomized trials.

Management of respiratory distress in moderate and late preterm infants: clinical trajectories in the Neobs study.

Management of respiratory distress (RD) in the extremely preterm newborn meets recommendations. Few data are available concerning the management and the clinical course of moderate and late preterms with RD. Clinical course and management among moderate (30-33 weeks (wks) of gestation) and late preterms (34-36 wks) were assessed in the Neobs study, a French neonatal observational cohort study (2018) of preterms with RD in the first 24 h of life. Clinical course was defined as stable (use of non-invasive ventilation (NIV) only), initially severe (initial use of invasive ventilation (IV)), and worsening (switch off IV after NIV support). Surfactant therapy instillation and withdrawal of all ventilator support at 72 h were recorded. Among moderate (n = 279) and late (n = 281) preterms, the clinical course was similar (p < 0.27): stable (82.1 and 86.8%), worsening (11.8% and 9.3%), and initially severe RD (6.1% and 3.9%), respectively. Surfactant was administered more frequently in the moderate versus late preterm groups (28.3% vs 16.7%; p < 0.001). The recommended surfactant dose (200 mg/kg) was administered in 53.3-83.3% of moderate and 42.1-63.2% of late preterms according to the clinical course. Withdrawal of ventilatory support at 72 h was observed in 40.0% and 70.0% of moderate and late preterms, respectively (p < 0.05), and was significantly (p < 0.001) associated with clinical course (the minus proportion among the worsening group). CONCLUSION: While the proportion of clinical course pattern is similar in moderate and late preterm infants, the management of RD varies with gestational age, with late preterm infants being managed later in life and moderate premature infants weaned from ventilation at a later stage. WHAT IS KNOWN: • There is a lack of clear guidance on the management of respiratory distress (RD) in moderate-to-late preterm infants. • Neobs was a multicentre, observational study designed to characterise the real-world management of moderate-to-late preterm infants with RD in France. WHAT IS NEW: • Secondary analyses of Neobs study data found that ventilatory support strategies were dependent on gestational age despite a similar clinical course. • At 30-33 weeks of gestation (wks), infants were more likely to receive non-invasive ventilation at delivery, while 34-36 wks infants were more likely to be managed using a wait-and-see approach.

Early factors associated with continuous positive airway pressure failure in moderate and late preterm infants.

To determine the early factors associated with continuous positive airway pressure (CPAP) failure in moderate-to-late preterm infants (32 + 0/7 to 36 + 6/7 weeks' gestation) from the NEOBS cohort study. The NEOBS study was a multi-center, prospective, observational study in 46 neonatal intensive care units in France, which included preterm and late preterm infants with early neonatal respiratory distress. This analysis included a subset of the NEOBS population who had respiratory distress and required ventilatory support with CPAP within the first 24 h of life. CPAP failure was defined as the need for tracheal intubation within 72 h of CPAP initiation. Maternal and neonatal clinical parameters in the delivery room and clinical data at 3 h of life were analyzed. CPAP failure occurred in 45/375 infants (12%), and compared with infants with CPAP success, they were mostly singletons (82.2% vs. 62.1%; p < 0.01), had a lower Apgar score at 10 min of life (9.1 ± 1.3 vs. 9.6 ± 0.8; p = 0.02), and required a higher fraction of inspired oxygen (FiO2; 34.4 ± 15.9% vs. 22.8 ± 4.1%; p < 0.0001) and a higher FiO2*positive end-expiratory pressure (PEEP) (1.8 ± 0.9 vs. 1.1 ± 0.3; p < 0.0001) at 3 h. FiO2 value of 0.23 (R2 = 0.73) and FiO2*PEEP of 1.50 (R2 = 0.75) best predicted CPAP failure. The risk of respiratory distress and early CPAP failure decreased 0.7 times per 1-week increase in gestational age and increased 1.7 times with every one-point decrease in Apgar score at 10 min and 19 times with FiO2*PEEP > 1.50 (vs. ≤ 1.50) at 3 h (R2 of the overall model = 0.83).  Conclusion: In moderate-to-late preterm infants, the combination of singleton pregnancy, lower Apgar score at 10 min, and FiO2*PEEP > 1.50 at 3 h can predict early CPAP failure with increased accuracy. What is Known: •Respiratory distress syndrome (RSD) represents an unmet medical need in moderate-to-late preterm births and is commonly treated with continuous positive airway pressure (CPAP) to reduce mortality and the need for additional ventilatory support. • Optimal management of RSD is yet to be established, with several studies suggesting that identification of predictive factors for CPAP failure can aid in the prompt treatment of infants likely to experience this failure. What is New: •Secondary analysis of the observational NEOBS study indicated that oxygen requirements during CPAP therapy, especially the product of fraction of inspired oxygen (FiO2) and positive end-expiratory pressure (PEEP), are important factors associated with early CPAP failure in moderate-to-late term preterm infants. •The combination of a singleton pregnancy, low Apgar score at 10 minutes, and high FiO2*PEEP at 3 hours can predict early CPAP failure with increased accuracy, highlighting important areas for future research into the prevention of CPAP failure.

Activity-dependent modulation of NMDA receptors by endogenous zinc shapes dendritic function in cortical neurons.

NMDA receptors (NMDARs) have been proposed to control single-neuron computations in vivo. However, whether specific mechanisms regulate the function of such receptors and modulate input-output transformations performed by cortical neurons under in vivo-like conditions is understudied. Here, we report that in layer 2/3 pyramidal neurons (L2/3 PNs), repeated synaptic stimulation results in an activity-dependent decrease in NMDAR function by vesicular zinc. Such a mechanism shifts the threshold for dendritic non-linearities and strongly reduces LTP. Modulation of NMDARs is cell and pathway specific, being present selectively in L2/3-L2/3 connections but absent in inputs originating from L4 neurons. Numerical simulations highlight that activity-dependent modulation of NMDARs influences dendritic computations, endowing L2/3 PN dendrites with the ability to sustain non-linear integrations constant across different regimes of synaptic activity like those found in vivo. Our results unveil vesicular zinc as an important endogenous modulator of dendritic function in cortical PNs.

Photochemical control of drug efficacy - a comparison of uncaging and photoswitching ifenprodil on NMDA receptors.

Ifenprodil is an important negative allosteric modulator of the N-methyl-D-aspartate (NMDA) receptors. We have synthesized caged and photoswitchable derivatives of this small molecule drug. Caged ifenprodil was biologically inert before photolysis, UV irradiation efficiently released the drug allowing selective inhibition of GluN2B-containing NMDA receptors. Azobenzene-modified ifenprodil, on the other hand, is inert in both its trans and cis configurations, although in silico modeling predicted the trans form to be able to bind to the receptor. The disparity in effectiveness between the two compounds reflects, in part, the inherent ability of each method in manipulating the binding properties of drugs. With appropriate structure-activity relationship uncaging enables binary control of effector binding, whereas photoswitching using feely diffusable chromophores shifts the dose-response curve of drug-receptor interaction. Our data suggest that the efficacy of pharmacophores having a confined binding site such as ifenprodil can be controlled more easily by uncaging in comparison to photoswitching.

Early correction of synaptic long-term depression improves abnormal anxiety-like behavior in adult GluN2B-C456Y-mutant mice.

Extensive evidence links Glutamate receptor, ionotropic, NMDA2B (GRIN2B), encoding the GluN2B/NR2B subunit of N-methyl-D-aspartate receptors (NMDARs), with various neurodevelopmental disorders, including autism spectrum disorders (ASDs), but the underlying mechanisms remain unclear. In addition, it remains unknown whether mutations in GluN2B, which starts to be expressed early in development, induces early pathophysiology that can be corrected by early treatments for long-lasting effects. We generated and characterized Grin2b-mutant mice that carry a heterozygous, ASD-risk C456Y mutation (Grin2b+/C456Y). In Grin2b+/C456Y mice, GluN2B protein levels were strongly reduced in association with decreased hippocampal NMDAR currents and NMDAR-dependent long-term depression (LTD) but unaltered long-term potentiation, indicative of mutation-induced protein degradation and LTD sensitivity. Behaviorally, Grin2b+/C456Y mice showed normal social interaction but exhibited abnormal anxiolytic-like behavior. Importantly, early, but not late, treatment of young Grin2b+/C456Y mice with the NMDAR agonist D-cycloserine rescued NMDAR currents and LTD in juvenile mice and improved anxiolytic-like behavior in adult mice. Therefore, GluN2B-C456Y haploinsufficiency decreases GluN2B protein levels, NMDAR-dependent LTD, and anxiety-like behavior, and early activation of NMDAR function has long-lasting effects on adult mouse behavior.

Altered zinc sensitivity of NMDA receptors harboring clinically-relevant mutations.

Recent human genetic studies have identified a surprisingly high number of alterations in genes encoding NMDA receptor (NMDAR) subunits in several common brain diseases. Among NMDAR subunits, the widely-expressed GluN2A subunit appears particularly affected, with tens of de novo or inherited mutations associated with neurodevelopmental conditions including childhood epilepsies and cognitive deficits. Despite the increasing identification of NMDAR mutations of clinical interest, there is still little information about the effects of the mutations on receptor and network function. Here we analyze the impact on receptor expression and function of nine GluN2A missense (i.e. single-point) mutations targeting the N-terminal domain, a large regulatory region involved in subunit assembly and allosteric signaling. While several mutations produced no or little apparent effect on receptor expression, gating and pharmacology, two showed a drastic expression phenotype and two resulted in marked alterations in the sensitivity to zinc, a potent allosteric inhibitor of GluN1/GluN2A receptors and modulator of excitatory synaptic transmission. Surprisingly, both increase (GluN2A-R370W) and decrease (GluN2A-P79R) of zinc sensitivity were observed on receptors containing either one or two copies of the mutated subunits. Overexpression of the mutant subunits in cultured rat neurons confirmed the results from heterologous expression. These results, together with previously published data, indicate that disease-causing mutations in NMDARs produce a wide spectrum of receptor alterations, at least in vitro. They also point to a critical role of the zinc-NMDAR interaction in neuronal function and human health.